Solid phase preparation of amines

ABSTRACT

A method for the solid phase preparation of an amine by a novel synthesis is described where a diol is monoalkylated with a chloromethyl resin followed by reaction with N,N&#39;-carbonyldimidazole to afford a resin-bound tertiary-alkoxycarbonyl-imidazole which is subsequently N-alkylated and then sequentially treated with appropriate building blocks and reagents to afford a resin-bound amine which affords the desired amine after treatment with an acid as well as other valuable intermediates used in the process.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.08/965,567, filed Nov. 6, 1997 which is regular application ofProvisional Application Serial No. 60/030,550, filed Nov. 13, 1996.

BACKGROUND OF THE INVENTION

The present invention relates to a method for the solid phase synthesisof an amine, more particularly, the present invention relates to amethod of synthesis of primary and secondary amines and α-amino estersuseful as pharmaceutical agents.

Most of the existing resin attachment strategies used in solid phaseorganic synthesis (SPOS) have been determined by those specialties suchas peptide, oligosaccharide, and oligonucleotide synthesis which havehad the longest history in successful utilization of SPOS. For example,there are many resin attachment strategies for carboxylic acids that areattributable to solid phase peptide synthesis (Merrifield R. B., J. Am.Chem. Soc., 1963;85:2149; Steward J. M., Young J. D., Solid PhasePeptide Synthesis, Pierce Chemical Co., Rockford, Ill. 1984:9-14).Similarly oligosaccharide chemistry has provided methods to attachalcohols to resins by forming an ether linkage (Gait M. J., ed.,Oligonuclentide Synthesis, IRL Press, Oxford, 1984; Frechet J. M. J., inPolymer-Supported Synthesis of Oligosaccharides, P. Hodge and D. C.Sherrington, eds., Wiley, New York: 1980:407-34). Recently, solid phasemethodology has been applied to the synthesis of a wide variety ofnon-oligomeric molecules (Terrett N. K., Gardner M., Gordon D. W.,Kobylecki R. J., Steele J., Tetrahedron, 1995;51:8135; Thompson L. A.,Ellman J. A., Chem. Rev., 1996;96:555) but often the synthesis of suchsmall organic molecules is restricted by the availability of linkingstrategies. A number of articles describing new resin linker strategies,including tetrahydro-pyranyl- (Thompson L. A., Ellman J. A., TetrahedronLett., 1994;35:9333), silyl- (Routledge A., Wallis M. P., Ross K. C.,Fraser W., Bioorg. Med. Chem. Lett., 1995;5:2059; Plunkett M. J., EllmanJ. A., J Org. Chem., 1995;60:6006; Randolph J. T., McClure K. F.,Danishefsky S. J., J. Am. Chem. Soc., 1995;117:5712), sulfonyl- (BackesB. J., Virgilio A. A., Ellman J. A., J. Am. Chem. Soc., 1996;118:3055;Beaver K. A., Siegmund A. C., Spear K., Tetrahedron Lett.,1996;37:1145), benzyloxycarbonyl- (Pande C. S., Gupta N., Bhardwaj A.,J. Appl. Polym. Sci., 1995;56:1127; Hauske J. R., Dorff P., TetrahedronLett., 1995;36:1589), and ADCC-linked solid supports (Bannwarth W.,Huebscher, Barner R. W., Bioorg. Med. Chem. Lett., 1996;6:1525) havebeen published.

The object of the present invention is the use of a resin linker towhich amino groups may be anchored for solid phase syntheses of avariety of heterocyclic molecules. Desirable properties of the linkerinclude stability to strongly basic conditions, temperatures as high as100° C., and strong nucleophiles. Lastly, the linker should be cleavedunder reasonably mild conditions.

We have found that the solid phase equivalent of a tertiary-butoxycarbonyl (t-Boc) protecting group fulfill these requirements. Thus,resin bound tertiary alcohols have been prepared by a two step synthesisfrom polystyrene-divinylbenzene (Wang S. S., Merrifield R. B., J. Am.Chem. Soc., 1969;91:6488) and chloromethylpolystyrene-divinylbenzene(Merrifield resin) (Wang S. S., J. Org. Chem., 1975;40:1235). These havebeen elaborated to a phenyl carbonate derivative and reacted withhydrazine to give a solid supported tert-alkoxycarbonylhydrazide whichis used in the synthesis of C-terminal hydrazides of peptides. The useof these literature methods in the Boc-like anchoring of amines to solidsupports has not reported, presumably because of difficulties achievingquantitative loading of amines via the tert-alkyl-phenylcarbonate moietywhich is a relatively unreactive acylating agent.

SUMMARY OF THE INVENTION

Accordingly, a first aspect of the present invention is a method for thesynthesis of an amine which comprises:

Step (a) treating a compound of Formula 2 ##STR1## wherein n is aninteger of 2 to 5 with a resin of Formula 3 ##STR2## wherein P is astyrene/divinylbenzene copolymer in the presence of a base and solventto afford a compound of Formula 4 ##STR3## wherein P and n are asdefined above;

Step (b) treating a compound of Formula 4 with 1,1'-carbonyldiimidazolein the presence of a base and a solvent to afford a compound of Formula5 ##STR4## wherein P and n are as defined above;

Step (c) treating a compound of Formula 5 sequentially with methyltrifluoromethanesulfonate (MeOTf) and a tertiary amine base in a solventto afford in situ a compound of Formula 6 ##STR5## wherein P and n areas defined above;

Step (d) sequentially adding the appropriate building blocks andcarrying out the appropriate reactions to synthesize an carbamate ofFormula 8 ##STR6## wherein P and n are as defined above;

Step (e) treating a compound of Formula 8 with an acid in a solvent toafford an amine.

A second aspect of the present invention is a novel intermediate ofFormula 4 ##STR7## wherein P is a styrene/divinylbenzene copolymer and nis an interger of 2 to 5.

A third aspect of the present invention is a novel intermediate ofFormula 5 ##STR8## wherein P is a styrene/divinylbenzene copolymer and nis an integer of 2 to 5.

DETAILED DESCRIPTION OF THE INVENTION

In this invention, the term "amine" means a primary or secondaryaliphatic, alicyclic, aromatic, heterocyclic, or heteroaromatic amineexcluding amines that cannot be protected with a tertiary butoxycarbonylgroup in greater than 700 yield by reaction with one equivalent ofdi-tertiary butyl dicarbonate in a solution phase reaction.

"Aliphatic amine" refers to an amine containing an alkyl group whereinthe term "alkyl" means a straight or branched hydrocarbon radical havingfrom 1 to 12 carbon atoms optionally substituted with one or morecarbonyl groups or carbonyalkyl groups or optionally wherein one or moreof the carbon atoms is replaced with a N, S, or O atom and includes, forexample, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl,n-decyl, undecyl, dodecyl, and the like; or an amine containing analkenyl group wherein the term "alkenyl" means a straight or branchedunsaturated hydrocarbon radical having from 2 to 12 carbon atoms andincludes, for example, ethenyl, 2-propenyl, 1-butenyl, 2-butenyl,1-pentenyl, 2-pentenyl, 3-methyl-3-butenyl, 1-hexenyl, 2-hexenyl,3-hexenyl, 3-heptenyl, 1-octenyl, 1-nonenyl, 1-decenyl, 1-undecenyl,1-dodecenyl, and the like; or an amine containing an alkynyl groupwherein the term "alkynyl" means a straight or branched triple bondedunsaturated hydrocarbon radical having from 2 to 12 carbon atoms andincludes, for example, ethynyl, 2-propynyl, 1-butynyl, 2-butynyl,3-butynyl, 1-pentynyl, 3-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl,3-heptynyl, 1-octynyl, 2-octynyl, 1-nonynyl, 2-nonynyl, 3-nonynyl,4-nonynyl, 1-decynyl, 2-decynyl, 2-undecynyl, 3-undecynyl, 3-dodecynyl,and the like.

"Alicyclic amine" refers to an amine containing a cycloalkyl groupwherein the term "cycloalkyl" means a saturated hydrocarbon ring whichcontains from 3 to 12 carbon atoms, for example, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, and the like; or anamine containing a cycloalkylalkyl group wherein the term"cycloalkylalkyl" means a saturated hydrocarbon ring attached to analkyl group wherein alkyl is as defined above. The saturated hydrocarbonring contains from 3 to 12 carbon atoms. Examples of such arecyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, adamantylmethyland the like.

"Aromatic amine" refers to an amine containing an aryl group wherein theterm "aryl" means an aromatic radical which is a phenyl group, a benzylgroup, a naphthyl group, a biphenyl group, a pyrenyl group, ananthracenyl group, or a fluorenyl group and the like, unsubstituted orsubstituted by 1 to 3 substituents selected from alkyl as defined above,alkoxy as defined above, thioalkoxy as defined above, hydroxy, thiol,nitro, halogen, amino, ##STR9## wherein alkyl is as defined above,##STR10## wherein alkyl is as defined above, ##STR11## wherein alkyl isas defined above, or aryl; or an amine containing a arylalkyl groupwherein an aryl group is attached to an alkyl group wherein alkyl is asdefined above, for example, benzyl and the like.

"Heterocyclic amine" refers to an amine containing a cycloalkyl groupwherein one or more of the carbon atoms is replaced with a N, S, or Oatom, for example, 2- or 3-tetrahydrothieno, 2- or 3-tetrahydrofurano,2- or 3-pyrrolidino, 2-, 4-, or 5-thiazolidino, 2-, 4-, or5-oxazolidino, 2-, 3-, or 4-piperidino, N-morpholinyl orN-thiamorpholinyl, and the like; or an amine containing acycloalkylalkyl group wherein one or more of the carbon atoms isreplaced with a N, S, or O atom wherein cycloalkylalkyl is as definedabove, for example, N-morpholinylethyl, and the like.

"Heteroaromatic amine" refers to an amine containing a heteroaryl groupwherein the term "heteroaryl" means a heteroaromatic radical which is 2-or 3-thienyl, 2- or 3-furanyl, 2- or 3-pyrrolyl, 2-, 4-, or5-imidazolyl, 3-, 4-, or 5-pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or5-isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or5-1,2,4-triazolyl, 4- or 5-1,2,3-triazolyl, tetrazolyl, 2-, 3-, or4-pyridinyl, 3-, 4-, or 5-pyridazinyl, 2-pyrazinyl, 2-, 4-, or5-pyrimidinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-,6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-,4-, 5-, 6-, or 7-benzo b!thienyl, or 2-, 4-, 5-, 6-, or 7-benzoxazolyl,2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 5-, 6-, or7-benzothiazolyl, unsubstituted or substituted by 1 to 2 substituentsselected from alkyl as defined above, aryl as defined above, alkoxy asdefined hereinafter, thioalkoxy as defined hereinafter, hydroxy, thiol,nitro, halogen, formyl, amino, ##STR12## wherein alkyl is as definedabove, ##STR13## wherein alkyl is as defined above, ##STR14## whereinalkyl is as defined above or phenyl; or an amine containing aheteroarylalkyl group wherein a heteroaryl group is attached to an alkylgroup wherein alkyl is as defined above.

The terms "alkoxy" and "thioalkoxy" are O-alkyl or S-alkyl as definedabove for alkyl.

The following Table 1 provides a list of abbreviations and definitionsthereof used in the present specification.

                  TABLE 1    ______________________________________    Abbreviation  Solvents and Reagents    ______________________________________    AcOH          Acetic acid    AcOMe         Methyl acetate    Ac.sub.2 O    Acetic anhydride    BnNCS         Benzyl isothiocyanate    n-BuOH        n-Butanol    Bu.sub.3 SnN.sub.3                  Tri-n-butyl stannyl azide    CDl           1,1'-Carbonyldiimidazole    CH.sub.2 Cl.sub.2                  Dichloromethane    DMF           Dimethylformamide    DMAP          4-Dimethylaminopyridine    1,2-DCE       1,2-Dichloroethane    (iPr).sub.2 EtN                  Diisopropylethylamine    HCl           Hydrochloric acid    KOH           Potassium Hydroxide    KO.sup.t Bu   Potassium tert butoxide    Merrifield Resin                  Chloromethylated divinylbenzene cross-                  linked polystyrene i.e., 1% to 2%                  divinylbenzene cross-linked    MeOH          Methanol    MeI           Methyl iodide    MeLi          Methyl lithium    MeOTf         Methyl trifluoromethanesulfonate                  (Methyl triflate)    MeNO.sub.2    Nitromethane    N.sub.2       Nitrogen    NH.sub.2 NH.sub.2                  Hydrazine    PH(CH.sub.2).sub.3 I                  1-Iodo-3-Phenylpropane    PhCH.sub.2 CN Phenylacetonitrile    Py            Pyridine    THF           Tetrahydrofuran    TFA           Trifluoroacetic acid    Et.sub.3 N    Triethylamine    H.sub.2 O     Water    P             Styrene/divinylbenzene copolymer    ______________________________________

The present invention discloses a homologous series of novel resins (5,n=5, 4, 3, and 2) for anchoring of amines by tert-alkoxycarbonylation.These resins are conveniently prepared in two steps from Merrifieldresin and are stable to long-term storage. In situ activation bystepwise sequential treatment with MeOTf and a tertiary amine base suchas, for example, Et₃ N and the like allows anchoring of a wide varietyof amines to a polymeric support for further solid phase synthesis.Subsequent sequential addition of suitable building blocks and reagentsunder suitable reaction conditions affords the synthesis of the desiredamines. Cleavage of the amines is readily accomplished under acidicconditions which are reasonably mild. The slightly different behavior ofeach homolog could make more convenient the use of one or anotherdepending on the nature of the loading amine and the synthetic sequenceinvolved. The commercial availability of 3-methyl-1,3-butanediol (2,n=2) and relative ease of removal of linker fragments after cleavagegenerally make 5.sub.(n=2) the preferred resin within the series.

The process of the present invention in its first aspect is outlined inScheme 1.

Thus, regiospecific monoalkylation of diols 2a-d by Merrifield resin (1%to 2% divinylbenzene cross-linked) is a simple, one step approach to thesynthesis of support bound tertiary alcohols that provides a range ofcarbon chain lengths between the linking functionality and the polymericsupport. Thus, 6-methyl-1,6-heptanediol (2, n=5) (Buendia J., Bull. Soc.Chim. Fr., 1966;9:2778), 5-methyl-1,5-hexanediol (2, n=4) (Lehmann J.,Marquardt N., Liebigs Ann. Chem., 1988:827), and4-methyl-1,4-pentanediol (2, n=3) (Lehmann J., Marquardt N., Synthesis,1987:1064) are prepared by the addition of excess MeLi to theappropriate lactone (1, n=5, 4, or 3) and 3-methyl-1,3-butanediol (2,n=2) is obtained commercially. Treatment of each diol with an equimolaramount of potassium t-butoxide generates the corresponding monoalkoxideswhich are alkylated by Merrifield resin (3) to yield a homologous seriesof solid supported t-alkanols (4, n=5, 4, 3, or 2). Loading was verifiedby elemental analysis which, within experimental error (±0.4% Cl), isconsistent with nearly quantitative loss of Cl. Attempted acetylation(Ac₂ O/pyridine) of 4.sub.(n=4) affords a polymer which does not displaya carbonyl stretch in its infrared (IR) spectrum, providing strongevidence for regiospecific reaction of Merrifield resin with the primaryalcohol. Significant resin cross-linking is not suspected with any ofthese diols based upon results with subsequent reactions.

Reaction of 4 with N,N'-carbonyldiimidazole (CDI) and4-(dimethylamino)pyridine (DMAP) affords the resin-boundtert-alkoxycarbonyl imidazole 5, as verified by nitrogen analysis andthe presence of a carbonyl absorption in the IR spectrum at 1750 cm⁻¹.Confirmation of the level of acylation was afforded by the amount ofimidazolium trifluoroacetate obtained upon cleavage with 10% TFA/CH₂Cl₂. In general, the reaction with CDI is efficient but notquantitative. Repeating the reaction does not significantly enhance thenitrogen content of the resin or increase the amount of imidazoliumtrifluoracetate recovered upon cleavage. The support-boundtert-alkoxycarbonyl imidazoles (5) are stable polymers but also poortert-alkoxycarbonylating reagents. For example, 5.sub.(n=4) does notacylate leucine methyl ester under a variety of conditions, includingthose reported for the preparation of resin bound benzyl carbamates(N-methyl-morpholine, 60° C., 4 hours) (Hauske J. R., Dorff P.,Tetrahedron Lett., 1995;36:1589).

The N-alkylation of imidazolides is known to greatly enhance theirreactivity as acyl transfer agents (Watkins B. E., Kiely J. S., RapoportH., J. Am. Chem. Soc., 1982;104:5702; Saha A. K., Schultz P., RapoportH., J. Am. Chem. Soc., 1989;111:4856; O'Connell J. F., J. Org. Chem.,1992;57:4775). Existing literature discloses the use of methyltrifluoromethane sulfonate (MeOTf) as alkylating reagent, and THF(O'Connell J. F., Rapoport H., J. Org. Chem. 1992;57:4775) or MeNO₂(Saha A. K., Schultz P., Rapoport H., J. Am. Chem. Soc., 1989;111:4856)as solvent. Tetrahydrofuran was initially the solvent of choice due toits better resin swelling properties. Treatment of 5.sub.(n=4) withMeOTf (300 mol %) for 30 minutes at 10° C. generates the correspondingresin bound tert-alkoxycarbonyl(3-methyl-imidazolium) triflate6.sub.(n=4), which is reacted in situ with amines to produce resin boundtert-alkyl carbamates (8). Cleavage (10% TFA/CH₂ Cl₂) of 8d.sub.(n=4)and removal of solvents in vacuo returned the starting amines as theirTFA salts with no contamination by imidazolium trifluoroacetate.Alternatively, 1,2-dichloroethane (DCE) can be used in place of THF.When DCE is used, the amount of MeOTf is reduced to 170 mol % and theremaining excess is quenched with Et₃ N (500 mol %) prior to addition ofthe primary amine (600 mol %). Therefore, sequential treatment of asuspension of 5 in DCE with MeOTf, followed by Et₃ N, followed by anamine is the preferred method for preparation of 8.

The length of the carbon chain between the benzylic ether and carbamategroups in 8 affects the ease of isolation of amine salt upon cleavage(Table 2). Treatment of a homologous series (n=5, 4, 3, and 2) of 8dwith 10% TFA/CH₂ Cl₂ and concentration of the filtrate at reducedpressure gives crude 7d·TFA. Examination of these crude products byProton Nuclear Magnetic Resonance Spectroscopy (¹ H NMR) shows thepresence of contaminating linker fragments with the higher threehomologs (n=5, 4, and 3) whereas pure 7d·TFA is observed with the lowesthomolog (n=2). With the homologs where n=4 and 3, these linker fragmentsare sufficiently volatile so as to be removed by more rigorous vacuumdrying at room temperature. Similar conditions did not permit the readyremoval of linker fragments with the highest homolog (n=5). Identitiesof these linker fragments have not been conclusively established but ¹ HNMR spectra of these crude product mixtures suggest that some of theextraneous signals can be accounted for by the presence of cyclic ethersresulting from the intramolecular participation of the benzylic oxygenatom in the cleavage. Interestingly, the hydroxy group of 7d does notparticipate in the cleavage, since neither bicyclic urethane nor etheranalogs of 7d are observed by ¹ H NMR. Moreover, acetylation (Ac₂ O/Py)of support-bound tert-alkyl carbamate 8d.sub.(n=4) followed by cleavageprovided 9 as the only product; therefore, 6.sub.(n=4) preferentiallyreacts with an amino group in the presence of a hydroxy group (Scheme2).

Table 3 exemplifies the solid phase anchoring of a variety of amines anda-amino acid esters by reaction with 6.sub.(n=2 or 4) using thisstrategy. Primary and secondary amines 7a-d react efficiently with6.sub.(n=2 or 4), affording nearly quantitative conversion to 8a-d in3.5 hours, regardless of the linker length. The efficiency of couplingwas determined by the mass of amine salt recovered after TFA cleavage.It is noteworthy that the shortest linker (n=2) consistently requireslonger TFA treatment (4.5 hours) than any of the longer homologs (≦3hours) to complete the cleavage reaction. Tertiary amino, hydroxy, andether groups present in 7a-d are compatible with the couplingconditions. The secondary aniline 7e, being less nucleophilic and moresterically hindered, defines a limitation in the ability of 6 to anchoramines. In this case the shorter linker (n=2) appears to afford superioranchoring of 7e as compared to the longer linker (n=4), a fact that maybe related to increased stability of 6.sub.(n=2) as compared to6.sub.(n=4) during the longer coupling time employed (≦7 hours).

The HCl salts of 7f-g were neutralized in situ with Et₃ N prior tocoupling with 6.sub.(n=4 or 2). An intermediate coupling time of 5.5hours gives excellent yields of the TFA salts upon cleavage. Methionineethyl ester (7h) gives a 4:1 mixture of 7h·TFA and 10 (Scheme 3) uponcleavage of 8h.sub.(n=2) whereas only 7h TFA was obtained from thelonger homolog, 8h.sub.(n=4). Acid catalyzed cleavage of3-methyl-2-butenoxymethyl resin to generate an allylic carbocation whichis quenched by the thioether, is a likely explanation for the formation10. The lack of such a sulfonium impurity from 8h.sub.(n=4) is likelythe result of the cyclic ether formation discussed previously. The useof a 3 M HCl solution that is prepared from acetyl chloride and DCM/MeOH(3:2) for cleavage eliminates the sulfonium byproduct, affording 7h.HClupon evaporation.

Schemes 4 and 5 depict the synthesis of a heteroaromatic andheterocyclic amine using the method of the present invention.

The starting resin bound tertiary alkyl carbamates in Schemes 2 to 5i.e., 8d, 8h, 8f, and 13 are prepared using methodology similar to thatdisclosed in Scheme 1.

The following nonlimiting examples illustrate the inventors' preferredmethod for preparing compounds of the present invention. ##STR15##

                  TABLE 2    ______________________________________    Variables Depending on the Alkyl Chain, n                   Removal Conditions for the    Alkyl Chain, n Linker Fragments from 7d.TFA    ______________________________________    5              Vacuum (2.5 mm Hg), 15 hours. A                   fragment remains.    4              Vacuum (2.5 mm Hg), 15 hours.    3              Vacuum (2.5 mm Hg), 2 hours.    2              Not required    ______________________________________

                                      TABLE 3    __________________________________________________________________________    tert-Alkoxycarbonylation of Amines 7                            8                     Alkyl         mmol/g of    Amine 7          Chain, n                          % N                             mmol N/g                                   cleaved amine    __________________________________________________________________________     ##STR16##    1                4 2  0.79 1.22                             0.56 0.87                                   0.59 0.85    2 #STR17##       4 2  0.48 2.19                             0.53 0.78                                   0.57 0.76    3 #STR18##       4 2  1.01 1.25                             0.68 0.88                                   0.68 0.84    4 #STR19##       4 2  0.96 1.19                             0.69 0.85                                   0.69 0.89    5 #STR20##       4 2  0.56 1.00                             0.40 0.71                                   0.29 0.68    6 #STR21##       4 2  0.78 1.11                             0.55 0.79                                   0.59 0.86    7 #STR22##       4 2  0.89 1.18                             0.63 0.83                                   0.51 0.77    8 #STR23##       4 2  0.92 1.12                             0.66 0.80                                   0.60 0.76.sup.a    9 #STR24##       4 2  1.57 2.07                             0.56 0.74                                   0.50 0.69    __________________________________________________________________________     .sup.a Cleavage conditions: 3 M HCl/CH.sub.2 Cl.sub.2, MeOH, AcOMe

EXAMPLE 1 General Procedure for the Preparation of Diols

(2.sub.(n=5)) (Buendia J., Bull. Soc. Chim. Fr., 1996;9:2778),2.sub.(n=4) (Lehmann J, Marquardt N. Liebigs. Ann. Chem., 1988:827), and2.sub.(n=3) (Lehmann J, Marquardt N. Synthesis, 1987:1064)

A 1.4M MeLi/diethyl ether solution (250 mol %) was added to a solutionof lactone 1 (100 mol %) in dry THF (1.7 mL/mmol) cooled to -78° C. Themixture was stirred for 30 minutes at -78° C. and for 6 hours whilewarming to room temperature. Acetic acid (250 mol %) was added, and thesuspension was stirred overnight at room temperature. After filtration,the filter cake was rinsed with THF, and the filtrates evaporated togive the crude diol 2 which was purified by vacuum distillation.

EXAMPLE 2 General Procedure for the Preparation of Resin-boundTert-alkanols (4)

A 1M KO^(t) Bu/THF (300 mol %) solution was added to a solution of thediol 2 (300 mol %) in dry THF (2.5 mL/mmol), cooled to 0° C. Thesolution was stirred at 0° C. for 45 minutes and for 3 hours whilewarming to room temperature. Merrifield resin (100 mol % of chlorinesites, L=1.35 mmol/g) was added and the suspension shaken for 3.5 daysat room temperature. After filtration, the resin-bound tert-alkanol 4was washed with THF (4 times), 1/1 DMF/H₂ O (2 times), DMF (2 times),1/1 DMF/H₂ O (2 times), DMF (2 times), THF (2 times), CH₂ Cl₂ (2 times),and dried. Analysis showed that Cl was absent.

EXAMPLE 3 General Procedure for the Preparation of Resin-boundTert-alkoxycarbonyl-imidazole (5)

DMAP (50 mol %) and CDI (400 mol %) were added to a suspension of theresin 4 (100 mol % of tert-alkanol sites) (The theoretical loading oftert-alkanol was calculated based upon the Cl content of the startingMerrifield resin, assuming the observed Cl displacement is due toexclusive monoalkylation by 1°-alcohol.) in dry DMF (4.5 mL/mmol). themixture was shaken for 24 hours at room temperature and filtered. Theresin-bound tert-alkoxycarbonylimidazole 5 was washed with CH₂ Cl₂ (3times), THF (3 times), CH₂ Cl₂ (3 times), and dried. Analysis showed thepresence of nitrogen.

EXAMPLE 4 General Procedure for the Preparation of Resin-boundTert-alkoxycarbonyl-3-methylimidazolium Triflates (6)

Methyl triflate (170 mol %) was added to a suspension of the resin 5(100 mol % of carbonylimidazole sites) in dry 1,2-DCE (20 mL/mmol),cooled to 10° C. The mixture was stirred for 15 minutes at thistemperature and for 5 to 10 minutes while warming to room temperature.After addition of Et₃ N (500 mol %), stirring was continued for anadditional 5 minutes and the suspension used directly as thetert-alkoxy-carbonylating/anchoring reagent.

EXAMPLE 5 General Procedure for the Preparation of Resin-boundTert-alkyl Carbamates (8.sub.(n=4) and 8.sub.(n=2) From Amines

The amine 7 (600 mol %) was added neat or as a solution in CH₂ Cl₂, to astirred suspension at room temperature of the resin-boundtert-alkylcarbonyl (3-methyllimidazolium) triflate 6 (100 mol %)prepared as above. The mixture was shaken for 3.5 hours at roomtemperature and filtered. The resin-bound tert-alkyl carbamate 8 waswashed with THF (3 times), 1/1 THF/MeOH (3 times), THF (3 times), CH₂Cl₂ (3 times), and dried.

Resin 8a.sub.(n=4) : IR 1717 cm⁻¹

Resin 8a.sub.(n=2) : IR 1716 cm⁻¹

Resin 8b.sub.(n=4) : IR 1714 cm⁻¹

Resin 8b.sub.(n=2) : IR 1713 cm⁻¹

Resin 8c.sub.(n=4) : IR 1688 cm⁻¹

Resin 8c.sub.(n=2) : IR 1680 cm⁻¹

Resin 8d.sub.(n=4) : IR 1670, 1655 cm⁻¹

Resin 8d.sub.(n=2) : IR 1696, 1663 cm⁻¹

Resin 8e.sub.(n=4) : IR 1698 cm⁻¹

Resin 8e.sub.(n=2) : IR 1698 cm⁻¹

EXAMPLE 6 General Procedure for the Preparation of Resin-boundTert-alkyl Carbamates (8.sub.(n=4) and 8.sub.(n=20)) from AminoEsters.HCl

Et₃ N (600 mol %) was added to a solution/suspension of the aminoester.HCl 7.HCl (600 mol %) in CH₂ Cl₂ (9 mL/mmol) and the resultingsuspension filtered. The amino ester solution was transferred viasyringe to a stirred suspension at room temperature of the resin-boundtert-alkoxycarbonyl-3-methyllimidazolium triflate 6 (100 mol %) preparedas above. The mixture was shaken for 5.5 hours at room temperature andfiltered. The resin-bound tert-alkyl carbamate 8 was washed with THF (3times), 1/1 THF/MeOH (3 times), THF (3 times), CH₂ Cl₂ (3 times), anddried.

Resin 8f.sub.(n=4) : IR 1717 (broad) cm⁻¹

Resin 8f.sub.(n=2) : IR 1744, 1720 cm⁻¹

Resin 8g.sub.(n=4) : IR 1734, 1717 cm⁻¹

Resin 8g.sub.(n=2) : IR 1734 (broad) cm⁻¹

Resin 8h.sub.(n=4) : IR 1733, 1716 cm⁻¹

Resin 8h.sub.(n=2) : IR 1733, 1717 cm⁻¹

Resin 8i.sub.(n=4) : IR 1734, 1716 cm⁻¹

Resin 8i.sub.(n=2) : IR 1732 (broad) cm⁻¹

EXAMPLE 7 General Procedure for Cleavage of Resin-bound Tert-alkylCarbamates (8.sub.(n=4) and 8_(n=2)))

Resin-bound tert-alkyl carbamates 8.sub.(n=4) and 8.sub.(n=2) weretreated with 10% TFA/CH₂ Cl₂ (2.5 mL/100 mg of resin) for 3 and 4.5hours, respectively, and filtered. For both types of resin, the resinwas rinsed with CH₂ Cl₂ (3 times), MeOH (2 times) and the filtratesevaporated and dried (vacuum, overnight) to give back amine 7, as itsTFA salt. The ¹ H NMR spectra of the cleaved amines were identical tothose obtained from authentic samples of ammonium trifluoroacetate7·TFA.

EXAMPLE 8 Cleavage of Resin-bound Tert-alkyl Carbamate (8h.sub.(n=2))

Acetyl chloride (10.2 mL, 0.14 mol) was added to a 3/2 CH₂ Cl₂ /MeOH (40mL) solution, cooled to 0° C. The resin 8h.sub.(n=2) (36 mg) was treatedwith the HCl solution (2.5 mL) for 4.5 hours and filtered. The resin wasrinsed with CH₂ Cl₂ (4 times), and the filtrates evaporated and dried(vacuum, overnight) to give back methionine ethyl ester (7h), as its HClsalt (8 mg). A ¹ H NMR spectrum of the cleaved ammonium hydrochloride7h. HCl was identical to the one obtained from an authentic sample ofmethionine ethyl ester.HCl.

EXAMPLE 9 3-(Acetoxymethyl)piperidinium Trifluoroacetate (9·TFA)(European Patent Application, EP 468231 A2, 1992)

Acetic anhydride (0.2 mL, 2.12 mmol) was added to a suspension of theresin 8d.sub.(n=4) (171 mg, L=0.69 mmol/g) in pyridine (1.6 mL), and themixture was shaken at room temperature for 24 hours. After filtration,the resin was washed with CH₂ Cl₂ (3 times), THF (3 times), 1/1 THF/MeOH(3 times), THF (3 times), CH₂ Cl₂ (3 times), and dried. Weight of resin:175 mg. IR 1740, 1645 cm⁻¹ ;

Analysis Found: C, 84.14; H, 1.87, 0.98.

A portion of the resin (59 mg) was treated with 10% TFA/CH₂ Cl₂ (2.5 mL)for 3 hours and filtered. The resin was rinsed with CH₂ Cl₂ (3 times),MeOH (2 times), and the filtrates were evaporated and dried (highvacuum, overnight) to give 9·TFA (9.3 mg).

¹ H NMR: δ 4.07 (dd, J=11.3, 5.2, 1H), 3.96 (dd, J=11.2, 7.2, 1H), 3.37(2d, J=14.5, 14.1, 2H), 2.91 (dt, J=2.9, 12.7, 1H), 2.77 (t, J=12.2,1H), 2.13 (m, 1H), 2.05 (s, 3H), 1.99-1.67 (m, 3H), 1.36 (m, 1H).

EXAMPLE 104-Benzyl-5-(1-amino-3-methylbutyl)-3-methylthio-1,2,4-triazoleTrifluoroacetate (12)

Step (a) Resin-bound N-(tert-alkoxycarbonyl)-leucine Hydrazide (11)

To a suspension of resin-bound N-(tert-alkoxy-carbonyl)-leucine methylester 8f (Example 6) (L=0.72 mmol/g, 2.07 g) in n-butanol (8.0 mL) wasadded anhydrous hydrazine (2.0 mL) and the mixture shaken at roomtemperature for 6.5 hours. After filtration, the resin was washed withTHF and MeOH. The last sequence of washes was repeated twice and finallythe resin was rinsed with CH₂ Cl₂ (3 times) and dried to giveresin-bound acid hydrazide 11 (1.95 g). Analysis Found: C, 81.93; H,7.94; N, 3.26. In order to verify completion of the reaction, a portionof the resin 11 (41 mg) was cleaved (10% TFA/CH₂ Cl₂, room temperature,4.5 hours) and filtered. The resin was rinsed with CH₂ Cl₂ (3 times) andMeOH (twice). The filtrates were evaporated and dried (high vacuum,overnight) to provide leucine hydrazide·2TFA (11 mg, loading of resin 2:0.72 mmol/g).

¹ H NMR (CD₃ OD): δ 1.91 (t, J=7 Hz, 1H), 1.71 (m, 3H), 0.99 (2d, J=6.2Hz, 6H).

Step (b): 4-Benzyl-5-(1-amino-3-methylbutyl)-3-methylthio-1,2,4-triazoleTrifluoroacetate (12)

The resin acid hydrazide 11 (110 mg, L=0.72 mmol/g) and a solution ofbenzyl isothiocyanate (57 mg, 0.38 mmol) in DMF (3.0 mL) were mixed in apeptide vessel and shaken at room temperature overnight. After drainingoff the solution, the resin was washed with DMF (3×2 mL), CH₂ Cl₂ (3×2mL), THF (3×2 mL), and dried. A 3/2 dioxane/0.25M KOH solution (3.0 mL)was added to the resin and the mixture heated at 60° C. to 65° C. (waterbath) for 3 hours. After filtration the resin was washed with THF (3×2mL), MeOH (3×2 mL), THF (3×2 mL), and dried. To a suspension of theresin in a 0.16M (iPr)₂ EtN/dioxane solution (1.0 mL), was added a 0.40MMEI/dioxane solution (1.0 mL), and the mixture was shaken at roomtemperature for 3 hours. The reagent solution was drained off, and theresin was washed with THF (3×2 mL), MeOH (3×2 mL), THF (3×2 mL), CH₂ Cl₂(3×2 mL), and dried. The resin was treated with 10% TFA/CH₂ Cl₂ (2.5 mL)at room temperature for 4.5 hours and filtered. The resin was rinsedwith CH₂ Cl₂ (2×3 mL), MeOH (2×3 mL), and the filtrates evaporated anddried to afford the trifluoroacetate salt of the 3-thio-1,2,4-triazole12 (30 mg, 93% yield from resin 11).

¹ H NMR (CD₃ OD): δ 7.39 (m, 3H), 7.13 (d, J=7.6 Hz, 2H), 5.32 (s, 2H),4.46 (t, J=7.2 Hz, 1H), 2.72 (s, 3H), 1.72 (t, J=7.3 Hz, 2H), 1.43 (m,1H), 0.77 (d, J=6.5 Hz, 3H), 0.63 (d, J=6.6 Hz, 3H), MS (m/z) 291 (MH⁺).

EXAMPLE 11 5-(4-Phenylpiperidin-4-yl)-2-(3-phenylpropyl)-2H-tetrazoleTrifluoroacetate (16)

Step (a): Resin-bound 4-cyano-4-pbenylpiperidine (14)

A suspension of resin-bound bis(2-chloroethyl)-amine 13 (110 mg, 0.075mmol) in DMF (2 mL) is treated with phenylacetonitrile (20 mg, 0.17mmol) and mixed. A 1N solution of potassium tert-butoxide in THF (0.34mL, 0.34 mmol) is added, and the reaction is shaken at room temperaturefor 24 hours. The resin is filtered and washed successively with DMF, H₂O, MeOH, DMF, CH₂ Cl₂, MeOH, CH₂ Cl₂, and MeOH. It is then dried invacuo at 50° C. for 24 hours to afford 14.

Step (b): Resin-bound5-(4-phenylpiperidin-4-yl)-2-(3-phenylpropyl)-2H-tetrazole (15)

A suspension of 14 (0.075 mmol) in anhydrous dioxane (2 mL) is treatedwith tri-n-butylstannyl azide (75 mg, 0.23 mmol) and heated at refluxunder N₂ for 24 hours. After cooling to room temperature, the resin isfiltered and washed with anhydrous dioxane (2×3 mL). It is thensuspended in pyridine-CH₂ Cl₂ (1:1, 2 mL) and treated with1-iodo-3-phenylpropane (55 mg, 0.22 mmol), shaking at room temperaturefor 2 days. The resulting resin is filtered and washed successively withDMF, 10% aqueous citric acid solution, H₂ O, MeOH, CH₂ Cl₂, MeOH, CH₂Cl₂, hexane, and CH₂ Cl₂ to afford 15.

Step (c): 5-(4-Phenylpiperidin-4-yl)-2-(3-phenylpropyl)-2H-tetrazoleTrifluoroacetate (16)

The resin 15 (0.075 mmol) is treated with 10% TFA/CH₂ Cl₂ (2.5 mL) atroom temperature for 4.5 hours and filtered. The resin is rinsed withCH₂ Cl₂ (2×3 mL), MeOH (2×3 mL), and the combined filtrates areevaporated and dried to afford 16.

We claim:
 1. A method for the synthesis of an amine which comprises:Step (a) treating a compound of Formula 2 ##STR25## wherein n is an integer of 2 to 5 with a resin of Formula 3 ##STR26## wherein P is a styrene/divinylbenzene copolymer in the presence of a base and solvent to afford a compound of Formula 4 ##STR27## wherein P and n are as defined above; Step (b) treating a compound of Formula 4 with 1,1'-carbonyldiimidazole in the presence of a base and a solvent to afford a compound of Formula 5 ##STR28## wherein P and n are as defined above; Step (c) treating a compound of Formula 5 sequentially with methyl trifluoromethanesulfonate (MeOTf) and a tertiary amine base in a solvent to afford in situ a compound of Formula 6 ##STR29## wherein P and n are as defined above; Step (d) sequentially adding the appropriate building blocks and carrying out the appropriate reactions to synthesize an carbamate of Formula 8 ##STR30## wherein P and n are as defined above; Step (e) treating a compound of Formula 8 with an acid in a solvent to afford an amine.
 2. A method according to claim 1 wherein the resin of Formula 3 is Merrifield resin.
 3. A method according to claim 1 wherein the base in Step (a) is potassium tertiary butoxide.
 4. A method according to claim 1 wherein the solvent in Step (a) is tetrahydrofuran.
 5. A method according to claim 1 wherein the base in Step (b) is 4-dimethylaminopyridine.
 6. A method according to claim 1 wherein the solvent in Step (b) is dimethylformamide.
 7. A method according to claim 1 wherein the base in Step (c) is triethylamine.
 8. A method according to claim 1 wherein the solvent in Step (c) is 1,2-dichloroethane.
 9. A method according to claim 1 wherein the acid in Step (e) is trifluoroacetic acid.
 10. A method according to claim 1 wherein the solvent in Step (e) is dichloromethane. 